Thyroid hormones (THs) regulate metabolism and low TH levels can cause weight gain. The effects of TH are mediated by two specific receptor proteins, TRα1 and TRβ, which are present in most tissues of the body. While a defective TRβ causes the human disorder RTH (Resistance to TH), a patient with a defective TRα1 has not been found yet. To facilitate their identification, genetically modified mice with a mutated TRα1 have been generated. They are lean and burn more fat that normal mice, because the sympathetic nervous system (SNS), which relays information from the brain to the body especially under stress conditions, is overactive. The project aims to identify the molecular reason for the overactive SNS.They are lean and burn more fat that normal mice, because the sympathetic nervous system (SNS), which relays information from the brain to the body especially under stress conditions, is overactive. The project aims to identify the molecular reason for the overactive SNS.
Initially the integrity of the SNS from the brain to the fat tissue was investigated. It was found, that the fat tissue has all the required receptors to receive a sympathetic signal and that the SNS is properly connected to the fat. Thus the reason for the hyperactive SNS must be within the brain itself. To find differences between the brains of normal and mutant mice, a microarray analysis was used, which measures the activity level of more than 13.000 genes at the same time. We found six genes, which were less active in the mutant mice; two of these genes are responsible for maintaining the excitability of neurons. It still needs to be investigated whether this is the cause for a hyperactive SNS. Further experiments suggest that the defects in the brain occur during embryonal development. As treatment of the pregnant female mice with high doses of TH can reverse the defects in the developing embryonic brain, the studies gives valuable clues how to identify patients with a similar mutation and how to treat them properly.